Process for the preparation of ropinirole

ABSTRACT

A new process for the preparation of Ropinirole (1) and pharmaceutically acceptable hydrochloride salt thereof comprising reacting the compound (V) with nitromethane to obtain the compound of formula (II), which is reduced to compound (III) and alkylated to obtain compound (IV). The oxidation of the indole ring provides the compound of formula (I)

This application is a 371 filing of PCT/EP2004/011505, filed Oct. 13,2004, which claims priority from Spanish Application 200302382, filedOct. 14, 2003.

THE SECTION OF TECHNOLOGY WHICH THE INVENTION REFERS TO

The present invention provides a new process for the preparation ofRopinirole useful in the treatment of Parkinson's disease.

DESCRIPTION OF THE TECHNICAL STATUS

The compound 4-[2-(dipropylamino)ethyl]-1,3-dihydro-indol-2-onerepresented by formula I, commonly known as Ropinirole has been used asan active constituent drug, as the hydrochloride salt.

Processes for preparing Ropinirole have been described previously.Particularly, the patent number EP-113964 comprising the reduction,using catalytic hydrogenation under low or moderate pressure conditions,of the 2-nitrophenyl acetic acid followed by the cyclization of theintermediate created.

Alternative processes for the preparation of Ropinirole have also beendescribed later on. For example in documents EP-300614 and EP-526529 thereductive cyclization of nitrostyrene compounds carried out in thepresence of acetyl chloride and iron chloride is described.

Until now, all processes described for the preparation of Ropinirolehave long synthesis or some disadvantages for their application on anindustrial scale. For this reason, it is necessary to find analternative process for the preparation of Ropinirole and/or itspharmaceutically acceptable salts, which are suitable for thepreparation at industrial scale.

DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of thecompound of formula I

comprising reacting the compound of formula IV with an oxidising agent.

The compound of formula IV can be oxidised by any oxidising agentdescribed in the literature for the conversion of indole into2-oxindole. The oxidising agent can be selected from the groupconsisting of halogenating agents such as pyridinium tribromide (PTB), aN-halosuccinimide such as N-chlorosuccinimide (NCS) orN-bromosuccinimide (NBS) in an acidic medium such as acetic acid orhydrochloric acid; or a sulphoxide such as dimethyl sulphoxide (DMSO) ora long chained alkylsulphoxide such as dodecylmethyl sulphoxide ordecylmethyl sulphoxide in acidic medium such as for example hydrochloricacid can also be used.

This reaction is carried out in a suitable solvent depending on theoxidising agent, and at a temperature between room temperature andreflux temperature.

In a preferred embodiment of the process, the conversion of IV into I iscarried out with pyridinium tribromide (PTB) and in the presence of anacid, preferentially aqueous acetic acid.

In a preferred embodiment, the conversion of IV into I is carried outwith N-chlorosuccinimide (NCS) and mineral acid, preferentially aqueoushydrochloric acid.

Later, the compound of formula I can be converted into itspharmaceutically acceptable salts, for example its hydrochloride, bymeans of the conventional methods already described in the literatureas, for example processing with hydrochloric acid.

The compound of formula IV can be prepared by alkylation of the compoundIII,

by reaction with an alkylating agent of formula CH₃CH₂CH₂-L, wherein Lis a leaving group, optionally in the presence of a base. As a leavinggroup any group described in the literature can be used, preferablyhalogen, methanesulphonate, toluenesulphonate,trifluoromethanesulphonate or benzenesulphonate. A wide variety of basescan be used, preferably sodium bicarbonate, potassium bicarbonate,sodium carbonate or potassium carbonate. The reaction is carried out ina suitable solvent, for example toluene.

In a preferred embodiment of the process, the leaving group is halogenand the reaction is carried out in the presence of a base.

In a more preferred embodiment, the leaving group is iodine or bromineand the reaction is carried out in the presence of sodium bicarbonate.

Alternatively the compound of formula IV can be prepared from thecompound of formula III, by reaction with a carbonylic compound offormula CH₃CH₂COR¹ wherein R¹ can be OH or H, in the presence of areducing agent and in normal reductive amination conditions.

In a preferred embodiment of the process, the carbonylic compound isCH₃CH₂COR¹ wherein R¹ is OH and the reducing agent is sodiumborohydride.

The compound of formula III can be prepared by reducing compound II,

by reaction with a reducing agent, for example LiAlH₄, NaBH₄—BF₃.Et₂O,NaBH₄—BH₃, diisobutyl aluminium hydride, bis(2-methoxyethoxy)aluminiumhydride or by means of hydrogenation in the presence of a catalyst, forexample Pd/C, Pd(OH)₂ or PtO₂.H₂O.

In a preferred embodiment, the reducing agent isbis(2-methoxyethoxy)aluminium hydride and the reaction is carried out intoluene, tetrahydrofuran or their mixtures at a temperature between roomtemperature and reflux temperature of the solvent.

The compound of formula II, can be prepared by treatment of4-indolecarboxaldehyde V

with nitromethane, in the presence of a base, for example ammoniumacetate and optionally in a suitable solvent.

In a preferred embodiment of the process, the compound of formula II canbe prepared from compound of formula V by reaction with nitromethane inthe presence of ammonium acetate at the reflux temperature ofnitromethane.

The compound of formula V, is known and can be prepared by processesalready described in the literature, for example the method described byJoseph M. Muchowski in the Journal of Heterocyclic Chemistry 2000,37(5), 1293.

The following examples are only given by way of illustration of theinvention and not to be understood as limiting.

The following abbreviations have been used in the examples:

-   AcOEt: ethyl acetate-   THF: tetrahydrofuran-   DIBAH: diisobutyl aluminium hydride

EXAMPLE 1 4-(2-nitrovinyl)indole (II)

Ammonium acetate (5.8 g, 75 mmol) was added to a solution of4-indolcarboxaldehyde (V) (29 g, 200 mmol) in nitromethane (290 mL),which was stirred and refluxed for 3 h 30 min. The reaction mixtureobtained was diluted with AcOEt and washed with a saturated solution ofNaCl. The organic layer was dried and concentrated to dryness. Theresultant residue was washed with cyclohexane and the solid wasfiltered, washed and dried under vacuum to obtain, 30.8 g (82%) of4-(2-nitrovinyl)indole (II).

¹H-RMN (200 MHz, DMSO-d₆) δ: 6.90 (m, 1H, 3-H), 7.20 (t, J=7.8 Hz, 1H,2-H), 7.62 (m, 3H, Ar), 8.19 (d, J=14 Hz, 1H, Ar—CH═CH—NO₂), 8.42 (d,J=14 Hz, 1H, Ar—CH═CH—NO₂), 11.6 (broad, 1H, NH).

EXAMPLE 2 4-[(2-amino)ethyl]indole (III)

Method A:

A solution of 4-(2-nitrovinyl)indole (II) (10 g, 53.2 mmol) in THF (200mL) was added to a suspension of LiAlH₄ (12.1 g, 319.2 mmol) in THF (600mL) at 0° C. and under inert atmosphere. When the temperature reachedroom temperature, the reaction mixture was heated at the refluxtemperature and stirred at this temperature for 3 hours. Ice-water wasadded to the resultant suspension, which was filtered through Celite,concentrated and extracted with AcOEt. The organic layer was dried,filtered and concentrated to obtain, 6.9 g (81%) of4-[(2-amino)ethyl]indole (III).

¹H-RMN (200 MHz, CDCl₃/CD₃OD), δ: 2.06 (broad, 2H, NH₂), 3.06 (m, 4H,Ar—CH₂—CH₂—NH₂), 6.55 (m, 1H, 3-H), 6.90-7.30 (m, 4H, Ar), 9.0 (broad,1H, NH).

Method B:

A solution of 4-(2-nitrovinyl)indole (II) (3 g, 15.9 mmol) in THF (10ml) was added to a suspension of DIBAH (1M THF, 159 ml, 159 mmol) underan inert atmosphere and was stirred at room temperature for 30 min, thenit was heated at 60° C. and stirred for 5 hours. The obtained mixturewas cooled to 0° C., AcOEt, water and KOH 10% were added and theontained product was filtered. The aqueous layer was extracted withAcOEt and the organic layer was dried and evaporated to obtain4-[(2-amino)ethyl]indole (III).

Method C:

A solution of 4-(2-nitrovinyl)indole (II) (25 g, 132.8 mmol) in THF (325mL) was added to a solution of bis(2-methoxy)aluminium hydride intoluene 70% (385 g, 1333 mmol) in toluene (325 mL), the reaction mixturewas heated to 60-70° C. and at this temperature the THF was distilled.Then toluene (325 mL) was added and stirred at a temperature between60-70° C. for 2 hours. Once the reaction mixture had reached roomtemperature, it was cooled to 5-10° C. and then NaOH 5% (600 mL) wasslowly added. The organic layer was separated and the aqueous layer wasextracted with toluene. The organic layer was washed with HCl 1N and theresultant aqueous layer was basified with NaOH 20% and extracted withtoluene to obtain, 13 g (61%) of 4-[(2-amino)ethyl]indole (III).

EXAMPLE 3 4-[2-(dipropylamino)ethyl]indole (IV)

Method A:

NaBH₄ (4.8 g, 126.9 mmol) was added to a mixture of4-[(2-amino)ethyl]indole (III) (4 g, 24.9 mmol) and propionic acid (27.8mL, 374.4 mmol) under inert atmosphere previously heated at 60° C. andthe reaction mixture was stirred at 55-60° C. for 20 hours. When thereaction mixture reached room temperature, NaOH 2N (80 mL) was added andwas then washed with toluene. The organic layer was washed with NaOH 2Nto obtain, 5.2 g (85%) of 4-[2-(dipropylamino)ethyl]indole (IV).

¹H-RMN (200 MHz, CDCl₃) δ: 0.91 (t, J=7.3 Hz, 6H, CH₃), 1.55 (m, 4H,CH₂—CH₃), 2.53 (m, 4H, N—CH₂—CH₂—CH₃), 3.0 (m, 4H, Ar—CH₂—CH₂—N), 6.58(m, 1H, 3-H), 6.90-7.40(m, 4H, Ar), 8.50 (broad, 1H, —NH.

Method B:

A mixture of 4-[(2-amino)ethyl]indole (III) (2.0 g, 12.48 mmol),1-iodopropane (8.5 g, 50 mmol), NaHCO₃ (2.3 g, 27.4 mmol) in toluene (40mL) was stirred at reflux temperature for 21 h. NaHCO₃ (1.15 g, 13.7mmol) in water (20 mL) and 1-iodopropane (2.12 g, 12.47 mmol) were addedto the resultant mixture and was stirred at the same temperature for 6h. When the mixture reached room temperature, it was filtered and layerswere separated. The organic layer was washed with water (15 mL), dried,filtered and evaporated to obtain 2.53 g (83%) of4-[2-(dipropylamino)ethyl]indole (IV).

EXAMPLE 4 4-[2-(dipropylamino)ethyl]indol-2-one (I)

Method A:

A solution of pyridinium tribromide 90% (8.72 g, 24.5 mmol) in aceticacid 50% (50 mL) was added to a solution of4-[2-(dipropylamino)ethyl]indol (IV) (5 g, 20.5 mmol) in acetic acid 50%(100 mL) and was stirred at 50° C. for 3 h. When the resultant mixturereached room temperature, it was stirred at this temperature for 16 h.The reaction mixture was concentrated to obtain an aqueous residue,which was diluted with water (100 mL), basified with an aqueous solutionof NaOH 10% and extracted with AcOEt. The organic layer was dried,filtered and concentrated to obtain 4.3 g (81%) of4-[2-(dipropylamino)ethyl]indol-2-one (I).

¹H-RMN (200 MHz, CDCl₃) δ: 0.88 (t, 6H, CH₃), 1.47 (m, 4H, CH₂CH₃), 2.44(m, 4H, NCH₂CH₂CH₃), 2.67 (m, 4H, ArCH₂CH₂N), 3.50 (s, 2H, 3-H),6.75-7.18 (m, 3H, Ar)

The compound of formula I was purified and converted into itshydrochloride salt.

Method B:

N-chlorosuccinimide (2.52 g, 18.9 mmol) was added to a solution of4-[2-(dipropylamino)ethyl]indole (IV) (3 g, 12.28 mmol) in toluene (10mL) and was stirred at room temperature for 1 h. The resultant mixturewas washed with an aqueous solution of NaOH 5% and then an aqueoussolution of HCl 1N (30 mL) was added to the organic layer and was heatedat reflux temperature for 1 h. When the mixture reached roomtemperature, the organic layer was separated and the aqueous layer wasbasified with an aqueous solution of NaOH and extracted with AcOEt. Theorganic layer was dried, filtered and concentrated to obtain 2.1 g (66%)of 4-[2-(dipropylamino)ethyl]indol-2-one (I), which was purified andconverted into its hydrochloride salt.

1. A process for the preparation of Ropinirole of formula I or apharmaceutically acceptable salt thereof

comprising reacting a compound of formula IV

with an oxidizing agent and to form the compound of formula I optionallyconverting the compound of formula I into a pharmaceutically acceptablesalt thereof.
 2. A process for the preparation of Ropinirole of formulaI or a pharmaceutically acceptable salt thereof

comprising reacting a compound of formula V

with nitromethane to obtain a compound of formula II

reducing the compound of formula II to obtain a compound of formula III

alkylating the compound of formula III to obtain a compound of formulaIV

oxidizing the compound of formula IV to obtain the compound of formulaI; and optionally converting the compound of formula I into apharmaceutically acceptable salt thereof.
 3. A process according toclaim 1 or 2, wherein the oxidising agent is a halogenating agent in anacidic medium.
 4. A process according to claim 3, wherein thehalogenating agent is pyridinium tribromide of N-halosuccinimide.
 5. Aprocess according to claim 1 or 2, wherein the oxidising agent is asulphoxide in an acidic medium.
 6. A process according to claim 5,wherein the sulphoxide is dimethylsulphoxide or a long chainedalkylsulphoxide.
 7. A process according to claim 1 or 2, wherein theconversion of IV into I is carried out by treatment with pyridiniumtribromide in acetic acid and water.
 8. A process according to claim 1or 2, wherein the conversion of IV into I is carried out by treatmentwith N-chlorosuccinimide in an aqueous mineral acid.
 9. A processaccording to claim 1 or 2, wherein the compound of formula IV isprepared by reacting a compound of formula III

with an alkylating agent of formula CH₃CHCH₂CH₂-L, wherein L is aleaving group.
 10. A process according to claim 9, wherein the reactionof compound III with the alkylating agent is carried out in the presenceof a base.
 11. A process according to claim 10, wherein the base issodium bicarbonate, potassium bicarbonate, sodium carbonate or potassiumcarbonate.
 12. A process according to claim 9, wherein the leaving groupL is selected from the group consisting of halogens, methansulphonate,toluenesulphonate, trifluoromethanesulphonate and benzenesulphonate. 13.A process according to claim 9, wherein the leaving group is a halogen.14. A process according to claim 13, wherein the leaving group L isiodine or bromine.
 15. A process according to claim 14, wherein theleaving group L is iodine or bromine and the base is sodium bicarbonate.16. A process according to claim 1 or 2, wherein the compound of formulaIV is prepared by reacting a compound of formula III with a carbonyliccompound of formula CH₃CH₂COR¹, wherein R¹=OH or H and the reaction iscarried out in the presence of a reducing agent.
 17. A process accordingto claim 16, wherein R¹=OH and the reducing agent is sodium borohydride.18. A process according to claim 2, wherein the reducing agent isselected from the group consisting of LiAlH₄, NaBH₄—BF₃.Et₂O, NaBH₄—BH₃, diisobutylaluminum hydride, bis(2-methoxyethoxy)aluminumhydride or hydrogen in the presence of a catalyst.
 19. A processaccording to claim 18, wherein the reducing agent isbis(2-methoxyethoxy)aluminum hydride.
 20. A process according to claim19, wherein the reducing agent is bis(2-methoxyethoxy)aluminum hydrideand the reaction is carried out in toluene, tetrahydrofuran or amixtures thereof at a temperature between room temperature and thereflux temperature of a solvent in which the reaction is carried out.21. A process according to claim 2, comprising the preparation of thecompound of formula II from the compound of formula V

by reaction with nitromethane in the presence of a base.
 22. A processaccording to claim 21, wherein the base is ammonium acetate.